(1) Mixed features of Alzheimer's disease (AD) and Creutzfeldt-Jakob disesase (CJD) were present in a family with a Presenilin-1 mutation. In two members of a French family showing clinicopathologic features of both, AD and CJD, including substantial cerebral depositions of bA4 and PrP amyloid proteins, a pathogenic A-to-G substitution at codon 163 of the Presenilin-1 gene on chromosome 14q replacing histidine with arginine in the encoding protein, was detected. No pathogenic mutations were identified in the PRNP gene coding for prion protein. A silent substitution at codon 117 in case 1 and a polymorphic 24-nucleotide deletion in the area of tandem repeats in case 2 were present. This is unclear if the substitutions in the PRNP gene may have caused spongiform encephalopathy and PrP depositions. In addition, different mutations in the Presenilin-1 gene were identified in two separate families with early-onset Alzheimer's disease. (2) Genotype-phenotype correlations were found in familial spongiform encephalopathy (FSE) associated with expansion and contraction of a polymorphic 24-bp repeat in the PRNP gene. Twenty-one families with 95 FSE patients having 24-bp repeat expansion in the PRNP gene on chromosome 20p were analyzed. These patients, as a group, were found to express a unique variant of FSE with an earlier onset and significantly longer duration of illness as compared to other FSEs, a premorbid phase and slow progressive course. Cortical atrophy, localization of spongiform change predominantly in frontal and occipital areas, and presence of Congophilic and non- Congophilic PrP deposits were distinct pathologic features. A statistically significant correlation was established between the number of 24-bp repeats and the age of disease onset. Twenty-three individuals from 15 families had contraction of the 24-bp repeat (4 repeats instead of the normal 5). We determined 5 types of deletion, depending on the location of the deleted sequences. One of the haplotypes, R3-R4/129Met, was present in five cases of environmentally acquired Creutzfeldt-Jakob disease and may predispose to this condition. (3) We studied the frequency of the apolipoprotein E e4 allele in human spongiform encephalopathies (SE). ApoE-e4 allele has been previously shown to predispose to late onset sporadic Alzheimer's disease and was thought to increase the propensity for amyloid formation. Amyloid plaque formation is the central mechanism in several forms of SE. Five hundred and fifty-five patients with SE and unaffected control individuals were genotyped for ApoE using a modified technique. The results, based on a large number of tested SE patients compared to appropriate controls, indicated that ApoE does not play a significant role in predisposing to sporadic or familial SE.